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Molecular basis for Jagged-1/Serrate ligand recognition by the Notch receptor.

ABSTRACT: We have mapped a Jagged/Serrate-binding site to specific residues within the 12th EGF domain of human and Drosophila Notch. Two critical residues, involved in a hydrophobic interaction, provide a ligand-binding platform and are adjacent to a Fringe-sensitive residue that modulates Notch activity. Our data suggest that small variations within the binding site fine-tune ligand specificity, which may explain the observed sequence heterogeneity in mammalian Notch paralogues, and should allow the development of paralogue-specific ligand-blocking antibodies. As a proof of principle, we have generated a Notch-1-specific monoclonal antibody that blocks binding, thus paving the way for antibody tools for research and therapeutic applications.

SUBMITTER: Whiteman P

PROVIDER: S-EPMC3591638 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Molecular basis for Jagged-1/Serrate ligand recognition by the Notch receptor.

Whiteman Pat P de Madrid Beatriz Hernandez BH Taylor Paul P Li Demin D Heslop Rebecca R Viticheep Nattnee N Tan Joyce Zi JZ Shimizu Hideyuki H Callaghan Juliana J Masiero Massimo M Li Ji Liang JL Banham Alison H AH Harris Adrian L AL Lea Susan M SM Redfield Christina C Baron Martin M Handford Penny A PA

The Journal of biological chemistry 20130121 10

We have mapped a Jagged/Serrate-binding site to specific residues within the 12th EGF domain of human and Drosophila Notch. Two critical residues, involved in a hydrophobic interaction, provide a ligand-binding platform and are adjacent to a Fringe-sensitive residue that modulates Notch activity. Our data suggest that small variations within the binding site fine-tune ligand specificity, which may explain the observed sequence heterogeneity in mammalian Notch paralogues, and should allow the dev ...[more]

PMID: 23339193

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